Cancer-causing karyotypes: chromosomal equilibria between destabilizing aneuploidy and stabilizing selection for oncogenic function

Lin, Li; McCormack, Amanda; Nicholson, Joshua M.; Fabarius, Alice; Hehlmann, Rüediger; Sachs, Rainer K.; Duesberg, Peter H.

doi:10.1016/j.cancergencyto.2008.08.016

Cited by 54 publications

(73 citation statements)

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“…Since cancers are species with flexible karyotypes, they can generate new subspecies, such as metastases, by spontaneous karyotypic rearrangements, independent of mutation. 17,[47][48][49][50][51][52] This flexibility of cancer karyotypes is a consequence of an equilibrium between two competing forces: (1) inherited imbalances of normal mitosis genes destabilizing cancer karyotypes. These imbalances reflect the very karyotypic rearrangements that generated cancers from normal cells.…”

Section: Origin Of Metastasesmentioning

confidence: 99%

“…17 (2) Selection for cancer-specific autonomy stabilizing the flexible karyotypes of cancers within cancer-specific margins of autonomy. 17,51 Accordingly, cancers can generate new autonomous subspecies with new species-specific karyotypes by intrinsic chromosomal rearrangements, as, for example, metastases and drug-resistant subspecies 17,22,51,53 (Fig. 1).…”

Section: Origin Of Metastasesmentioning

confidence: 99%

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Origin of metastases: Subspecies of cancers generated by intrinsic karyotypic variations

et al. 2012

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Section: Origin Of Metastasesmentioning

confidence: 99%

Section: Origin Of Metastasesmentioning

confidence: 99%

Origin of metastases: Subspecies of cancers generated by intrinsic karyotypic variations

et al. 2012

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“…Dicha teoría ha sido corroborada en numerosos estudios citogenéticos de tumores sólidos. Los recientes trabajos de Duesberg et al (28,29) reevalúan los postulados de Boveri, utilizando modelos in vitro con células transformadas, en los que se ratifica que el cáncer se origina por aneuploidías (pérdida o ganancia de cromosomas) y que la inestabilidad cromosómica es proporcional al grado de la aneuploidía y al número de cromosomas afectados (6,29). En conclusión, Duesberg confirma que las alteraciones cromosómicas juegan un papel fundamental en la iniciación y progresión del cáncer, y que, además, los cromosomas de las células cancerosas son inestables por causa de la aneuploidía.…”

Section: Discussionunclassified

Detección de aneuploidías del cromosoma 17 y deleción del gen TP53 en una amplia variedad de tumores sólidos mediante hibridación in situ fluorescente bicolor

et al. 2010

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Detección de aneuploidías del cromosoma 17 y deleción del genTP53 en una amplia variedad de tumores sólidos mediante hibridación in situ fluorescente bicolor Introducción. El TP53 es un gen supresor de tumores localizado en la región cromosómica 17p13.1; controla el ciclo celular y se encuentra alterado en cerca de 50% de todas las neoplasias. Objetivos. Determinar las aneuploidías del cromosoma 17 y la deleción en el locus 17p13.1 del gen TP53, en diversos tumores sólidos primarios utilizando la técnica FISH-bicolor. Materiales y métodos. Se analizaron 38 muestras de diversos tipos de tumores sólidos primarios. Todas las muestras se disociaron mecánica y enzimáticamente con colagenasa al 0,2%, antes de la obtención de los núcleos interfásicos. La técnica de FISH-bicolor se realizó en núcleos interfásicos, mediante sondas marcadas directamente con fluorocromos para el centrómero del cromosoma 17 (CEP 17; señal verde; VYSIS) y para el locus específico del gen TP53 (LSI 17p13.1; señal naranja; VYSIS). Resultados. Se encontró que 63% (24/38) de las muestras tenían aneuploidías del cromosoma 17. La monosomía fue la aneuploidía más frecuente (75%; 18/24), seguida de la trisomía (17%; 4/24); la nulisomía y la tetrasomía fueron menos frecuentes. El 89,5% (34/38) de los casos presentaron deleción del gen TP53. Sólo cuatro casos fueron normales para el número de copias del cromosoma 17 y del gen TP53. El estudio histopatológico mostró que la mayoría de las muestras eran tumores malignos. Conclusiones. La aneuploidía del cromosoma 17 y la deleción en el locus 17p13.1 del gen TP53 son alteraciones muy frecuentes en los tumores sólidos. La técnica FISH-bicolor permite detectar simultáneamente alteraciones cromosómicas numéricas y estructurales en núcleos interfásicos.Palabras clave: aneuploidía, deleción cromosómica, gen Tp53, hibridación fluorescente in situ, neoplasias, inestabilidad cromosómica, heterogeneidad genética. Detection of chromosome 17 aneuplody and TP53 gene deletion in a broad variety of solid tumors by dual-color fluorescence in situ hybridization (FISH)Introduction. TP53 is a tumor suppressor gene located on chromosome 17p13.1. This gene is essential for the control of cell cycle and has been found altered in about 50% of all tumor types. Objective. The presence of aneuploidy of chromosome 17 and TP53 gene deletion at 17p13.1 locus was determined in primary solid tumors using the dual-color FISH (fluorescence in situ hybridization). Materials and methods. Thirty-eight samples consisted of several types of primary solid tumors. All samples were mechanically and enzymatically disaggregated with 0.2% collagenase prior to obtaining interphase nuclei. The dual-color FISH was performed using direct fluorescent labeling probes for the chromosome 17 centromere (green signal) and for the TP53 gene locus-specific (orange signal).Results. Characteristic aneuploidy on chromosome 17 was found in 63% (24/38) of the samples. Monosomy occurred most frequently (75%, 18/24), followed by trisomy (17%, 4/24); nullisomy and te...

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“…• The rapid-alteration approximation could give new insights into other scenarios, especially for human solid tumors and in vitro analogues, where an unexpected degree of karyotype stability is often found despite highly heterogeneous aneuploidy at each instant (Nowell, 1976;Eshleman et al, 1998;Macville et al, 1999;Roschke et al, 2002;Jin et al, 2005;Li et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

A Rapid-Mutation Approximation for Cell Population Dynamics

Sachs

Hlatky

2009

Bull. Math. Biol.

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Carcinogenesis and cancer progression are often modeled using population dynamics equations for a diverse somatic cell population undergoing mutations or other alterations that alter the fitness of a cell and its progeny. Usually it is then assumed, paralleling standard mathematical approaches to evolution, that such alterations are slow compared to selection, i.e., compared to subpopulation frequency changes induced by unequal subpopulation proliferation rates. However, the alterations can be rapid in some cases. For example, results in our lab on in vitro analogues of transformation and progression in carcinogenesis suggest there could be periods where rapid alterations triggered by horizontal intercellular transfer of genetic material occur and quickly result in marked changes of cell population structure.We here initiate a mathematical study of situations where alterations are rapid compared to selection. A classic selection-mutation formalism is generalized to obtain a "proliferation-alteration" system of ordinary differential equations, which we analyze using a rapid-alteration approximation. A system-theoretical estimate of the total-population net growth rate emerges. This rate characterizes the diverse, interacting cell population acting as a single system; it is a weighted average of subpopulation rates, the weights being components of the Perron-Frobenius eigenvector for an ergodic Markov-process matrix that describes alterations by themselves. We give a detailed numerical example to illustrate the rapid-alteration approximation, suggest a possible interpretation of the fact that average aneuploidy during cancer progression often appears to be comparatively stable in time, and briefly discuss possible generalizations as well as weaknesses of our approach.

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Cancer-causing karyotypes: chromosomal equilibria between destabilizing aneuploidy and stabilizing selection for oncogenic function

Cited by 54 publications

References 100 publications

Origin of metastases: Subspecies of cancers generated by intrinsic karyotypic variations

Origin of metastases: Subspecies of cancers generated by intrinsic karyotypic variations

Detección de aneuploidías del cromosoma 17 y deleción del gen TP53 en una amplia variedad de tumores sólidos mediante hibridación in situ fluorescente bicolor

A Rapid-Mutation Approximation for Cell Population Dynamics

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